CD40 signaling is well established to enhance development and maintenance of adaptive immunity. However, the role of CD40 signaling during innate immune responses is more poorly studied and an important role for CD40 signaling in rapid control of acute virus infections is not currently appreciated. Here, we provide strong preliminary findings that CD40 signaling is critical for early stimulation of innate immune pathways in peritoneal macrophages, resulting in control of acute viral infection. In these proposed studies, we will use both Ebola virus (EBOV) and a BSL2 model virus of EBOV to identify the CD40+ cellular compartment(s) required for protection and understand the breadth of cell populations that use CD40 signaling to control EBOV infection. Elucidation of these cell populations will elucidate targeted approaches that can lead to therapeutic interventions.